Byfavo
remimazolam
Species
MonkeyPig
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey and minipig
“In general, findings in the pivotal repeat-dose toxicity studies with the API in monkey and minipig were limited to expected pharmacology and local toxicity.”
Why that species
Pivotal monkey and minipig studies used infusion dosing with the clinical formulation
“These two pivotal studies were selected for detailed review because the study investigated infusion dosing with the clinical formulation.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The repeat dose toxicity of remimazolam dosed by the intravenous route, as a bolus injection, at 5, 10 and 20 mg/kg/day once daily for 4 weeks has been conducted, including a 2-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
4 (4-week minipig and monkey)
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
Pivotal GLP studies
4-week IV infusion studies in minipig and monkey with 2-week recovery
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
Route in tox
Intravenous (bolus and infusion)
“Repeated dose toxicity studies, up to 4 weeks duration, have been conducted in cynomolgus monkeys with administration of remimazolam by intravenous bolus and by intravenous infusion.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and in vivo rat micronucleus assays
“Genetic toxicology battery for the API was negative in the Ames assay, mouse lymphoma assay, and in vivo rat micronucleus test.”
Carcinogenicity
Not conducted
“Long-term animal studies have not been performed to evaluate the carcinogenic potential of remimazolam.”
Reproductive & developmental
Rat and rabbit EFD: no adverse embryo-fetal effects in surviving animals
“Regardless of these adverse effects to the pregnant female, in surviving animals, remimazolam had no adverse effects on embryo-fetal development up to 30 mg/kg/day in rat”
Safety pharmacology
Benzodiazepine-type sedation, respiratory depression and cardiovascular depression
“Remimazolam produced typical benzodiazepine-related pharmacodynamic effects including sedation, respiratory depression, and cardiovascular depression.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Byfavo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey
“Local toxicities included thickened intima and partially recoverable endothelial fibrosis of blood vessels at 2.5 mg/mL in monkey.”
Risksopen answer page →
Immune & cytokine safety
No immune system findings
“There were no findings indicating an influence of remimazolam on the immune system.”
Biodistribution & persistence
Very limited placental transfer; readily enters breast milk
“Placenta penetration of remimazolam and/or its derivatives was very limited and did not lead to a sustained exposure of the fetus. Remimazolam and/or its derivatives easily accessed breast milk; the concentrations determined in milk were linked to maternal plasma concentrations.”
Modality-specific risk
Inadequate rat DART exposure margins (short boluses below human exposure)
“Of specific concern, data from the rat studies did not provide acceptable safety margins as the DART studies were conducted with short boluses that resulted in systemic exposures below that in humans.”